Allergy and Sleep: Basic Principles and Clinical Practice [1st ed.] 978-3-030-14737-2;978-3-030-14738-9

Table of contents :
Front Matter ....Pages i-xv
Front Matter ....Pages 1-1
Sleep, Sleep Disorders, and Immune Function (Hui-Leng Tan, Leila Kheirandish-Gozal, David Gozal)....Pages 3-15
Overview of Basic Immunology (Barry J. Pelz, Joshua B. Wechsler)....Pages 17-30
Overview and Understanding of Basic Circadian Physiology (Sabra M. Abbott, Phyllis C. Zee)....Pages 31-41
Overview and Understanding of Human Circadian Immunology (Nurcicek Padem, Anna Fishbein)....Pages 43-58
Overview and Understanding of Allergic Reactions and Allergic Disease (Andrew M. Abreo, Kourtney G. Gardner, Jonathan A. Hemler)....Pages 59-64
Ontogeny of Sleep in Infants, Children, and Adolescents (Irina Trosman, Samuel J. Trosman, Stephen H. Sheldon)....Pages 65-74
Front Matter ....Pages 75-75
Screening for Allergic Disease in a Child with Sleep Disorder and Screening for Sleep Disturbance in Allergic Disease (Tanvi H. Mukundan)....Pages 77-85
Evaluation and Management of a Sleepy Child (Anne Marie Morse, Sanjeev V. Kothare)....Pages 87-104
Evaluation and Management of the Sleepless Child (Rafael Pelayo)....Pages 105-122
Evaluation and Management of Movement Disorders in Children (Luis E. Ortiz, Christopher Cielo)....Pages 123-135
Evaluation and Management of Allergic Disorders Related to Sleep Pathology (Innessa Donskoy, Stephen H. Sheldon)....Pages 137-150
Front Matter ....Pages 151-151
Sleep-Related Disturbances Commonly Associated with Asthma (Sofia Konstantinopoulou, Ignacio E. Tapia)....Pages 153-161
Obesity, Asthma, and Sleep-Related Breathing Disorders (Maria Teresa Coutinho, Daphne Koinis Mitchell)....Pages 163-174
Monitoring Asthma During Sleep: Methods and Techniques (Katalina Bertran, Trinidad Sánchez, Pablo E. Brockmann)....Pages 175-183
Asthma Treatment Outcome Measures (Manisha Witmans)....Pages 185-193
Guidelines for Management of Sleep-Related Breathing Disorders and Asthma (Daniel Cerrone, Emily Gillett, Sally Ward)....Pages 195-211
Front Matter ....Pages 213-213
Pathophysiology of Sleep-Disordered Breathing and Allergic Rhinitis (Fatima S. Khan)....Pages 215-226
Sleep-Related Breathing Disorders and Inflammation: TNF-α and IL-6 as Prototypic Examples (Leila Kheirandish-Gozal, Hui-Leng Tan, David Gozal)....Pages 227-245
Circadian Rhythm of Allergic Rhinitis, Skin Testing and Allergen Immunotherapy (Arjola Cosper, John Oppenheimer, Linda Cox)....Pages 247-252
Differentiating Upper Airways Resistance in Adenoid Hypertrophy, Allergic Rhinitis, and Obstructive Sleep Apnea: Imaging and Approaches (Sophie Shay, James W. Schroeder Jr.)....Pages 253-269
Allergic Rhinitis and Sleep: Approaches to Management (Camil Correia, Fuad M. Baroody)....Pages 271-292
Front Matter ....Pages 293-293
Sleep-Related Disorders Associated with Atopic Dermatitis (Namita Jain, Oriana Sanchez, Hrayr Attarian)....Pages 295-305
Sleep Disruption in Atopic Dermatitis (Duri Yun, Lacey L. Kruse)....Pages 307-315
Front Matter ....Pages 317-317
Sleep Dysregulation in Chronic Rhinosinusitis (Mahboobeh Mahdavinia, Anjeni Keswani)....Pages 319-328
Front Matter ....Pages 329-329
Behavioural Management (Charlie Tyack)....Pages 331-349
Chronotherapy (Laurie A. Manka, Richard J. Martin)....Pages 351-366
Melatonin, Sleep, and Allergy (Rui Guan, Roneil G. Malkani)....Pages 367-384
Pharmacologic Management of Allergic Disease and Sleep (Natalia M. Jasiak-Panek, Kevin T. Le, Thomas Moran, Sukhraj Mudahar)....Pages 385-407
Alternative/Integrative Medical Approaches in Allergy and Sleep: Basic Principles and Clinical Practice (Xiu-Min Li, Henry Ehrlich, Paul Ehrlich, Anne Maitland, Erin Thanik, Julia A. Wisniewski et al.)....Pages 409-422
Assessment and Therapies for Sleep and Sleep-Related Breathing Disorders Associated with Atopic Disease in Children: A Dental Perspective (Kevin L. Boyd)....Pages 423-434
Surgical Management of Allergic Disease to Treat Sleep Disturbance in Children and Adults (Matthew Purkey, Chris Gouveia, Bruce Tan)....Pages 435-449
Back Matter ....Pages 451-463

Citation preview

Allergy and Sleep Basic Principles and Clinical Practice Anna Fishbein Stephen H. Sheldon  Editors

123

Allergy and Sleep

Anna Fishbein  •  Stephen H. Sheldon Editors

Allergy and Sleep Basic Principles and Clinical Practice

Editors Anna Fishbein Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL USA

Stephen H. Sheldon Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL USA

ISBN 978-3-030-14737-2    ISBN 978-3-030-14738-9 (eBook) https://doi.org/10.1007/978-3-030-14738-9 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

The idea for this textbook arose during the implementation of our interdisciplinary allergy/sleep disorders clinic at the Ann & Robert H. Lurie Children’s Hospital of Chicago. In this clinic, we identify many children with allergic diseases, such as allergic rhinitis, asthma, atopic dermatitis, and other immunologically related problems that also have principal sleep-related complaints. In managing both allergic and sleep disorders, we gained insight into the impact these disciplines have upon each other. Comprehensive management requires attention to the underlying allergic disorder as well as identification and management of sleep-related problems. On the other hand, many children presenting to the Pediatric Sleep Medicine Center at Lurie Children’s Hospital have comorbid allergic symptomatology. Treatment only of the sleep-related difficulties does not result in optimal control of symptoms. Only after treatment of both the sleep-related difficulties and allergic pathology can treatment be personalized and optimized. This does not imply broad allergy testing in sleep patients but rather a symptom-directed approach. In diagnosing and managing both sleep and allergic disorders, the practitioner must recognize important relationships. First, primary sleep-related abnormalities may affect daytime functioning caused by pathologic processes during sleep or may exacerbate existing primary medical disorders. Through diagnosis and treatment of sleep-related abnormalities, adverse health outcomes might be avoided or treatment of the primary medical problem more effective. Second, sleep-related pathology can exist concomitantly with an allergic disorder. This requires therapeutic approaches to comorbid conditions in order to obtain an optimal outcome. Finally, the presence of sleep-related abnormalities occurring as a result of allergic disorders not only impacts the health and well-being of the affected individual but can have more widespread effects on the entire family, particularly in pediatrics. A child’s nocturnal sleep disruption can cause sleeplessness, daytime fatigue, and significant diurnal performance difficulties. Although our training is in pediatrics, authors of this book are experts in pediatric and adult disease and provide an overview of disease assessment and treatment approaches throughout the life-span. Chapter authors reflect the multidisciplinary practitioners required to assess and treat allergy and sleep disorders  – allergists, sleep medicine physicians, otolaryngologists, dermatologists, primary care physicians, pharmacists, psychologists, dentists, and other researchers.

v

vi

Preface

The book structure reflects our overall approach to comprehensive allergy and sleep care. First, in Part I, we provide a primer on the science of sleep, allergy, immunology, circadian rhythms, and circadian immunology. In Part II, the clinical science is addressed first by presenting symptoms in a case-based approach. Next, we address assessment and treatment by specific, common allergic diseases. Finally, disease, sleep, and circadian specific therapeutics are reviewed. Researching the association of allergy and sleep-related disorders led us to a paucity of literature. It is clear from clinical practice that children and adults with allergic disorders sleep poorly. In our sleep medicine center, it is common to see children with sleep disorders also suffer from allergy. When choosing topics for chapters to include in this text, there were many with abundant literature from which to draw. Still other topics revealed minimal evidence. It was decided to still include these chapters to begin discussion of the topic and overlap. It was not to provide answers but to stimulate questions for discussion and future research. It is hoped this textbook will provide insight into cause and effect as well as an understanding of the complex interactions healthcare practitioners face in order to provide optimal care to their patients and families. Chicago, IL, USA Chicago, IL, USA 

Anna Fishbein Stephen H. Sheldon

Contents

Part I Science of Sleep 1 Sleep, Sleep Disorders, and Immune Function ��������������������������������������   3 Hui-Leng Tan, Leila Kheirandish-Gozal, and David Gozal 2 Overview of Basic Immunology����������������������������������������������������������������  17 Barry J. Pelz and Joshua B. Wechsler 3 Overview and Understanding of Basic Circadian Physiology ��������������  31 Sabra M. Abbott and Phyllis C. Zee 4 Overview and Understanding of Human Circadian Immunology��������  43 Nurcicek Padem and Anna Fishbein 5 Overview and Understanding of Allergic Reactions and Allergic Disease ����������������������������������������������������������������������������������  59 Andrew M. Abreo, Kourtney G. Gardner, and Jonathan A. Hemler 6 Ontogeny of Sleep in Infants, Children, and Adolescents����������������������  65 Irina Trosman, Samuel J. Trosman, and Stephen H. Sheldon Part II Clinical Science 7 Screening for Allergic Disease in a Child with Sleep Disorder and Screening for Sleep Disturbance in Allergic Disease ����������������������  77 Tanvi H. Mukundan 8 Evaluation and Management of a Sleepy Child��������������������������������������  87 Anne Marie Morse and Sanjeev V. Kothare 9 Evaluation and Management of the Sleepless Child������������������������������ 105 Rafael Pelayo 10 Evaluation and Management of Movement Disorders in Children������ 123 Luis E. Ortiz and Christopher Cielo 11 Evaluation and Management of Allergic Disorders Related to Sleep Pathology������������������������������������������������������������������������ 137 Innessa Donskoy and Stephen H. Sheldon vii

viii

Contents

Part III Asthma 12 Sleep-Related Disturbances Commonly Associated with Asthma �������� 153 Sofia Konstantinopoulou and Ignacio E. Tapia 13 Obesity, Asthma, and Sleep-Related Breathing Disorders�������������������� 163 Maria Teresa Coutinho and Daphne Koinis Mitchell 14 Monitoring Asthma During Sleep: Methods and Techniques���������������� 175 Katalina Bertran, Trinidad Sánchez, and Pablo E. Brockmann 15 Asthma Treatment Outcome Measures���������������������������������������������������� 185 Manisha Witmans 16 Guidelines for Management of Sleep-­Related Breathing Disorders and Asthma ������������������������������������������������������������������������������ 195 Daniel Cerrone, Emily Gillett, and Sally Ward Part IV Allergic Rhinitis 17 Pathophysiology of Sleep-Disordered Breathing and Allergic Rhinitis���������������������������������������������������������������������������������� 215 Fatima S. Khan 18 Sleep-Related Breathing Disorders and Inflammation: TNF-α and IL-6 as Prototypic Examples������������������������������������������������ 227 Leila Kheirandish-Gozal, Hui-Leng Tan, and David Gozal 19 Circadian Rhythm of Allergic Rhinitis, Skin Testing and Allergen Immunotherapy������������������������������������������������������������������ 247 Arjola Cosper, John Oppenheimer, and Linda Cox 20 Differentiating Upper Airways Resistance in Adenoid Hypertrophy, Allergic Rhinitis, and Obstructive Sleep Apnea: Imaging and Approaches���������������������������������������������������� 253 Sophie Shay and James W. Schroeder Jr. 21 Allergic Rhinitis and Sleep: Approaches to Management���������������������� 271 Camil Correia and Fuad M. Baroody Part V Atopic Dermatitis 22 Sleep-Related Disorders Associated with Atopic Dermatitis ���������������� 295 Namita Jain, Oriana Sanchez, and Hrayr Attarian 23 Sleep Disruption in Atopic Dermatitis ���������������������������������������������������� 307 Duri Yun and Lacey L. Kruse Part VI Chronic Sinusitis 24 Sleep Dysregulation in Chronic Rhinosinusitis �������������������������������������� 319 Mahboobeh Mahdavinia and Anjeni Keswani

Contents

ix

Part VII Therapies for Sleep and Sleep-Related Breathing Disorders Associated with Atopic Disease 25 Behavioural Management ������������������������������������������������������������������������ 331 Charlie Tyack 26 Chronotherapy ������������������������������������������������������������������������������������������ 351 Laurie A. Manka and Richard J. Martin 27 Melatonin, Sleep, and Allergy ������������������������������������������������������������������ 367 Rui Guan and Roneil G. Malkani 28 Pharmacologic Management of Allergic Disease and Sleep������������������ 385 Natalia M. Jasiak-Panek, Kevin T. Le, Thomas Moran, and Sukhraj Mudahar 29 Alternative/Integrative Medical Approaches in Allergy and Sleep: Basic Principles and Clinical Practice���������������������������������� 409 Xiu-Min Li, Henry Ehrlich, Paul Ehrlich, Anne Maitland, Erin Thanik, Julia A. Wisniewski, and Danna Chung 30 Assessment and Therapies for Sleep and Sleep-Related Breathing Disorders Associated with Atopic Disease in Children: A Dental Perspective���������������������������������������������������������������������������������� 423 Kevin L. Boyd 31 Surgical Management of Allergic Disease to Treat Sleep Disturbance in Children and Adults�������������������������������������������������������� 435 Matthew Purkey, Chris Gouveia, and Bruce Tan Appendix: Food Allergy and Sleep ������������������������������������������������������������������ 451 Vinaya Ramesh Soundararajan and Anna Fishbein References ���������������������������������������������������������������������������������������������������������� 453 Index�������������������������������������������������������������������������������������������������������������������� 455

Contributors

Sabra M. Abbott, MD, PhD  Department of Neurology, Northwestern University, Chicago, IL, USA Andrew  M.  Abreo, MD  Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Hrayr  Attarian, MD  Department of Neurology, Sleep Medicine, Northwestern Medicine, Feinberg School of Medicine, Chicago, IL, USA Fuad M. Baroody, MD, FACS  Department of Surgery, Section of Otolaryngology-­ Head and Neck Surgery and Department of Pediatrics, The University of Chicago Medicine and The Comer Children’s Hospital, Chicago, IL, USA Katalina  Bertran, MD  Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile Kevin L. Boyd, DDS, MSc  Dentistry for Children and Families, Chicago, IL, USA Ann & Robert H. Lurie, Children’s Hospital of Chicago, Chicago, IL, USA Pablo  E.  Brockmann, MD, PhD  Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile Daniel  Cerrone, MD  Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA Danna Chung, MD  Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Christopher Cielo, DO, MS  Sleep Center, Department of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Camil Correia, MD  Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, IL, USA

xi

xii

Contributors

Maria Teresa Coutinho, PhD  Child and Family Psychiatry & Pediatrics, Brown Medical School, Bradley/Hasbro Children’s Research Center, Providence, RI, USA Linda  Cox, MD  Department of Medicine, University of Miami at Holy Cross Hospital, Fort Lauderdale, FL, USA Innessa Donskoy, MD, FAAP  Department of Pediatric Sleep Medicine, Advocate Children’s Hospital, Park Ridge, IL, USA Henry  Ehrlich, BA  Pediatric Allergy and Immunology, Jaffe Food Allergy Institute, Center for Integrative Medicine for Immunology and Wellness, Icahn School of Medicine at Mount Sinai, New York, NY, USA Paul  Ehrlich, MD  Department of Pediatrics, New York University Langone Medical Center, New York, NY, USA Anna  Fishbein, MD, MSci  Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Kourtney  G.  Gardner, MD  Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Emily Gillett, MD, PhD  Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA Chris  Gouveia, MD  Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA David  Gozal, MD, MBA  Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA Rui  Guan, MD  Institute of Neurological Sciences, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia Jonathan  A.  Hemler, MD  Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA Namita  Jain, MD, MPH  Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Natalia  M.  Jasiak-Panek, PharmD, BCPS  Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Anjeni  Keswani, MD, MSCI  Division of Allergy/Immunology, Department of Medicine, GW School of Medicine and Health Sciences, Washington, DC, USA Fatima  S.  Khan, MD  Department of Allergy and Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

Contributors

xiii

Leila  Kheirandish-Gozal, MD, MSc  Department of Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO, USA Sofia Konstantinopoulou, MD  Division of Pulmonary Medicine, Department of Pediatrics, Sheikh Khalyfa Medical City, Tibbiyya, Abu Dhabi, United Arab Emirates Sanjeev  V.  Kothare, MD  Pediatric Sleep Program, Department of Neurology, NYU Langone Medical Center, New York, NY, USA Lacey L. Kruse, MD  Departments of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Kevin T. Le, PharmD, BCPS  Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Xiu-Min  Li, MD  Department of Pediatrics, Pediatric Allergy and Immunology, Jaffe Food Allergy Institute, Center for Integrative Medicine for Immunology and Wellness, Icahn School of Medicine at Mount Sinai, New York, NY, USA Mahboobeh  Mahdavinia, MD, PhD  Allergy and Immunology Division, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA Anne Maitland, MD  Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Roneil  G.  Malkani, MD, MSCI  Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Laurie A. Manka, MD  Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA Richard J. Martin, MD  Department of Medicine, National Jewish Health, Denver, CO, USA Daphne Koinis Mitchell, PhD  Child and Family Psychiatry & Pediatrics, Brown Medical School, Bradley/Hasbro Children’s Research Center, Warren Alpert Medical School of Brown University, Providence, RI, USA Thomas  Moran, PharmD, BCPS  Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Anne  Marie  Morse, DO  Department of Child Neurology, Sleep Medicine, Geisinger Medical Center, Janet Weis Children’s Hospital, Danville, PA, USA Sukhraj  Mudahar, PharmD, BCPS  Department of Pharmacy, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Tanvi H. Mukundan, MD  Department of Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA

xiv

Contributors

Luis E. Ortiz, MD  Sleep Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Nurcicek Padem, MD  Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, IL, USA Rafael Pelayo, MD  Department of Psychiatry and Behavioral Sciences, Stanford Center for Sleep Sciences and Medicine, Stanford Sleep Medicine Center, Redwood City, CA, USA Barry  J.  Pelz, MD  Division of Asthma, Allergy, and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA Matthew  Purkey, MD  Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA Oriana  Sanchez, MD  Northwestern University Feinberg School of Medicine, Chicago, IL, USA Trinidad  Sánchez, MD  Department of Pediatric Cardiology and Pulmonology, Division of Pediatrics and Sleep Medicine Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile James  W.  Schroeder Jr., MD  Department of Surgery, Division of Otorhinolaryngology, Head and Neck Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Department of Otorhinolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Sophie Shay, MD  Division of Otolaryngology-Head and Neck Surgery, Ann and Robert H.  Lurie Children’s Hospital of Chicago, Northwestern McGaw Medical Center, Chicago, IL, USA Stephen  H.  Sheldon, DO, FAAP  Departments of Pediatrics & Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Sleep Medicine Center, Division of Pulmonary and Sleep Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA Vinaya  Soundararajan, MD  Department of Dermatology, Northwestern University, Chicago, IL, USA Bruce  Tan, MD  Department of Otolaryngology, Head & Neck Surgery, Northwestern Memorial Hospital, Chicago, IL, USA Hui-Leng Tan, MBBChir, MD  Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK Ignacio  E.  Tapia, MD, MS  Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

Contributors

xv

Sleep Center, Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Erin  Thanik, MD, MPH  Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA Irina Trosman, MD  Sleep Medicine Center, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Samuel  J.  Trosman, MD  Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Charlie Tyack, DClinPsy  Sleep Medicine Department, Evelina London Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK Sally  Ward, MD  Division of Pulmonology and Sleep Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA Joshua B. Wechsler, MD  Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Julia  A.  Wisniewski, MD  Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA Manisha Witmans, MD, FRCPC, FAASM  Division of Pediatric Pulmonology, Department of Pediatrics, The Stollery Children’s Hospital & University of Alberta Hospitals, Edmonton, AB, Canada Duri Yun, MD, MPH  Departments of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Phyllis  C.  Zee, MD, PhD  Department of Neurology, Northwestern Medicine Feinberg School of Medicine, Chicago, IL, USA

Part I Science of Sleep

1

Sleep, Sleep Disorders, and Immune Function Hui-Leng Tan, Leila Kheirandish-Gozal, and David Gozal

In this introductory chapter, our aim is not to provide comprehensive coverage of the topic, but rather highlight tantalizing snippets of interesting information regarding the paradigm of the busy cross talk between sleep, sleep disorders, and immune function, in the hope that it will pique the interest of the reader and stimulate ­further reading.

Sleep and Immune Function Immunological processes are regulated by sleep and circadian rhythms [1]. During sleep, downregulation of the hypothalamus–pituitary-adrenal (HPA) axis and reduced activity of the sympathetic nervous system (SNS) occur. Levels of cortisol, epinephrine, and norepinephrine decrease, whereas levels of growth hormone (GH), leptin, and prolactin increase. All of these hormones and many others support immune cell activation, proliferation, and differentiation and the production of pro-­ inflammatory cytokines such as IL-1, IL-12, TNF-α, and IFN-γ. Immune rhythms are also regulated by intrinsic cellular clocks which arise from conserved transcription-­translation feedback oscillator loops driven by a set of dedicated clock proteins. These circadian clocks regulate the rhythms of inflammatory processes by

H.-L. Tan Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK e-mail: [email protected] L. Kheirandish-Gozal (*) Department of Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO, USA D. Gozal Department of Child Health, University of Missouri School of Medicine, Columbia, MO, USA © Springer Nature Switzerland AG 2019 A. Fishbein, S. H. Sheldon (eds.), Allergy and Sleep, https://doi.org/10.1007/978-3-030-14738-9_1

3

4

H.-L. Tan et al.

selectively intruding into immune pathways and orchestrate the phenotype and specific activity of multiple cells including macrophages, lymphocytes, and natural killer cells. In accordance with such circadian-immune interactions, differentiated immune cells such as cytotoxic NK cells and terminally differentiated cytotoxic T lymphocytes increase their presence and activity during the day with increased prolonged wake periods. Since their activation can occur as a rapid response pattern and very quickly, this unique setup allows for the efficient and speedy combat of intruding antigens and organisms that are more likely to occur during the active waking phase. In contrast, undifferentiated or less differentiated immune cells, such as naïve and central memory T cells, peak during the night, when the more slowly evolving adaptive immune responses are initiated and propagated. Sleep, particularly slow-wave sleep, i.e., the predominant stage of sleep during the first half of the night, promotes the release of GH and prolactin, while cortisol and catecholamines are at trough levels. These conditions support not only the shift of the Th1/ Th2 cytokine balance toward that of Th1 but also enable the enhanced production of IL-12 by antigen-­presenting cells, a process that is essential for the activation of T helper cells and an increase in T helper cell proliferation. Herein lies an important facet of the role of sleep in the formation and maintenance of immunological memory [2]. By the time one reaches the end of a night’s sleep in the early hours of the morning, Th2 activity predominates [3]. From such observations, it follows that perturbation to sleep integrity, cycling, or duration is likely to alter this finely regulated and coordinated set of immune interactions, leading to disruption of the immune homeostatic processes. Interestingly, the relationship between the immune system and sleep is bidirectional, such that the immune response can reciprocally impact on sleep. For example, many infectious processes, particularly during the acute phase of the immune response, result in an increase in the duration of NREM sleep and concomitant decrease in REM sleep and wakefulness [4]. Cytokines such as IL-1β and TNF-α are produced as part of the acute phase immune response and can induce symptoms of fatigue and sleepiness and also promote non-rapid eye movement sleep [5]. This is postulated to be a mechanism by which organisms divert energy resources toward mounting a robust response against the infective challenge, and as such increased sleep activity is likely to improve the specific antimicrobial immune function response.

Sleep Deprivation and Its Impact on Immune Function A substantial portion of our understanding on the relationship between sleep and the immune system has been derived from experiments which curtail the duration of sleep in experimental subjects. The impact of acute sleep deprivation differs from that of chronic sleep restriction or deprivation. Prolonged sleep curtailment invokes the non-specific persistent production of pro-inflammatory cytokines, resulting in a

1  Sleep, Sleep Disorders, and Immune Function

5

state of chronic low-grade systemic inflammation, while concomitantly impairing host defense mechanisms, both of which have significant detrimental effects on health. Low-grade systemic inflammation is one of the common themes that will be pervasively invoked throughout this chapter and is a risk factor for cognitive, cardiovascular, and metabolic morbidity, especially when present in conjunction with obesity, another common condition in which low-grade systemic inflammation is frequently detected. It is a commonly held lay view that inadequate sleep makes one more prone to catching colds. This supposedly “old wives’ tale” is actually supported by experimental models. Prather et  al. recruited 164 healthy adult volunteers, objectively assessed their sleep duration for a week, then quarantined them, and administered nasal drops containing rhinovirus [6]. Participants who had shorter sleep duration (20  years. A surprising wide range of medications were being prescribed and recommended with little evidence-based data to support it. The authors concluded that insomnia is a significant clinical problem in children treated by child psychiatrists for a variety of behavioral, neurodevelopmental, and psychiatric conditions. In addition there was a worrisome highly variable clinical approach to insomnia children. Melatonin is frequently used for delayed sleep phase syndrome and jet lag as it may have a phase-setting effect on the body. In adults taking melatonin, small amounts prior to bedtime are thought to be effective in raising the plasma melatonin to normal levels. The doses which may be effective in children are unclear [35]. An analysis of over-the-counter melatonin in Canada raised strong concerns about the quality of the product [40]. Erland and colleagues analyzed melatonin by ultraperformance liquid chromatography in 30 commercial supplements. Melatonin content was found to range from −83% to +478% of the labelled content including within the same brand. Serotonin was found in 26% of the samples. Melatonin content did not meet the label within a 10% margin of the label claim in more than 71% of supplements. An accompanying commentary to this article called for greater regulation of the sale of melatonin [41]. This lack of regulation may cause the quality of over-the-counter melatonin to be highly variable. Melatonin has been used in children with sleeplessness due to circadian factors such as sleep phase delay disorder and blindness and patients with midline brain defects such as agenesis of corpus callosum as this may affect the pineal gland. Children with poor sleep associated with neurological syndromes have also had some positive outcomes [37]. A randomized trial of melatonin was compared to bright light treatment, and a control was done with 84 children (average age was 10 years old) [42]. The authors found that both melatonin and bright light treatment were able to shorten sleep latency but the effect was stronger with melatonin.

9  Evaluation and Management of the Sleepless Child

117

In clinical practice both of these treatment options can be combined depending on the clinical situation. Ramelteon, a melatonin receptor agonist, has been approved for use in patients 18 years and older with sleep-onset insomnia [43–45]. It has been reported to help the sleep of people with autistic spectrum disorder [44, 46]. It may be considered in adolescents with sleep phase delay syndrome. However no clinical trials are available for patients younger than 18 years old. There was at least one report of it being used for the treatment of night terrors and sleepwalking in children [47]. Tasimelteon is a melatonin receptor agonist which was released by the FDA for the treatment of non-24-hour sleep-wake disorder in 2014. It has an affinity for human melatonin receptors MT1 and MT2, with a higher affinity for the latter. The clinical trials were done in blind adults with a circadian disorder [48, 49]. Safety and efficacy have not been established in pediatric patients. There is a hypothetical possibility that this new medication may be useful to help entrain the sleep of children with significant circadian disruption to a more predictable schedule. However, to date there are no pediatric studies available. Benzodiazepines and benzodiazepine receptor agonist can be considered as therapeutic options to improve sleep [50]. The benzodiazepine, clonazepam, is available in low-dose sublingual wafers that allow for easier administration. Benzodiazepines are hypnotics that act as a GABA receptor agonist. The most commonly used benzodiazepine used in children for sleep is clonazepam. Clonazepam has been used for arousal parasomnias such as sleepwalking and sleep terrors in children [51]. Clonazepam may allow the child to sleep throughout the night and is thought to decrease the arousal threshold. This drug may be beneficial if this behavior is frequent and disturbing to the patient or family. A dose of clonazepam at 0.25–0.5 mg may be used. Benzodiazepines may lead to muscle relaxation, and therefore caution is advised in children with obstructive sleep apnea as it may exacerbate the condition. Selective benzodiazepine receptor agonists including zolpidem, eszopiclone, and zaleplon are thought to offer some advantages compared to nonselective benzodiazepines. These selective benzodiazepine receptor agonists at low dosages are thought to preserve the overall sleep architecture and are thought to have less insomnia rebound effects after discontinuation when compared to nonselective benzodiazepines. These medications only have FDA approval for use in patients older than 18 years old, and therefore the use of these medications in children is considered “off-label.” There are reports of zolpidem abuse among adolescents [52, 53].

Sleep and Allergies Sleep disorders in general and obstructive sleep apnea in particular are commonly encountered conditions in allergy practice. Obstructive sleep apnea along with the entire spectrum of sleep-disordered breathing (SDB) may present with sleeplessness. The clinician suspicion for SDB in a child should not limit solely to those that snore loudly or appear sleep and tired. Any nasopharyngeal obstruction from

118

R. Pelayo

rhinitis, nasal polyposis, or adenotonsillar hypertrophy may contribute to audible breathing and obstructive breathing events. An allergist does not need to limit their management of continuous positive airway pressure intolerance. In 2015, an Internet-based survey of active American Academy of Allergy, Asthma & Immunology members was performed to determine perceptions and practice regarding SDB. Only 7% of active members returned the survey (339 of 4881). Most of the respondents reported that SDB was a problem for at least a “substantial minority” (10–30%) of their adult patients and believed that medical therapy for upper airway inflammatory conditions could potentially help ameliorate sleep-related complaints. The authors supported “the connection between high-grade nasal congestion/adenotonsillar hypertrophy and obstructive sleep apnea, and at least in the case of pediatric patients, supported the use of anti-inflammatory medication in the initial management of obstructive sleep apnea of mild-to-moderate severity.” They called for allergists to be proactive role in the diagnosis and management of sleep-­ disordered breathing [54]. Children with atopic dermatitis can experience significant sleep disruption since it worsens at night. Epidemiologic findings of atopic dermatitis impaired growth. A sleep assessment is considered a crucial component of clinical management. Treatment options that address the sleep disturbance are future directions for research [55]. Although conditions with nasal obstruction or nocturnal eczema would be expected to disrupt sleep, sleep disorders are often underreported to physicians by patients and with allergies their families. A French prospective study of children and adults was done to characterize the sleep disorders associated with respiratory allergy to house dust mites at the time of initiation of immunotherapy. The study included 843 children older than age 5 suffering from dust mite allergy. The majority of the children (66%) reported that their sleep disorders prompted their medical consult. The most commonly observed sleep complaints for the children were snoring in 41%, poor-quality sleep (37%), and nocturnal awakening (28%). Difficulties falling asleep were reported by 25% of children. Children suffering from severe persistent allergic rhinitis experienced sleep complaints significantly more often than those with only intermittent or mildly persistent rhinitis. This study confirms that a sleep history should be part of the evaluation of allergies. This is particularly true when severe allergic rhinitis is present [56]. Clinical practice guidelines specifically recommend that clinicians should assess patients including children with a clinical diagnosis of allergic rhinitis for comorbid SDB [57]. SDB, in children with comorbid asthma, may exacerbate asthma control. A study of 408 children with an average age of 8 years found that sleep-disordered breathing and tonsillar hypertrophy were independent risk factors for poor control in these asthmatic children. The authors concluded that “tonsillar hypertrophy may have a role in the association between” sleep-disordered breathing and not-well-controlled asthma in childhood [58]. A systematic review to describe the relationship between asthma and SDB in children found children with asthma were more likely to develop habitual snoring and obstructive sleep apnea. Children with SDB were more likely to develop asthma. Asthma was associated with more severe OSA, and the presence

9  Evaluation and Management of the Sleepless Child

119

of SDB was associated with severe asthma. The authors concluded there was a bidirectional relationship between asthma and SDB and adenotonsillectomy appears to improve both conditions [59]. Some clinical populations may require closer attention. Zandieh and colleagues reported a group of 9565 urban adolescents. Compared to those without probable asthma, adolescents with probable asthma had 2.6 greater odds of reporting SDB symptoms which increased with severity. The authors concluded that among urban adolescents with self-reported SDB symptoms, there was an association with probable asthma and increased asthma severity. This is important since SDB treatment may improve asthma control [60]. The presence of comorbid asthma may be an important consideration when considering the treatment approach to SDB.  A study by Mukhatiyar and colleagues found that the comorbid asthma may help predict the efficacy of the adenotonsillectomy type. They compared the outcomes of intracapsular versus extracapsular adenotonsillectomy and found that the SDB was more likely to be refractory to treatment with intracapsular adenotonsillectomy compared with the extracapsular type [61].

Conclusions There are many reasons a child may be considered to be sleepless. Fortunately, the vast majority of these children can receive effective treatment after a careful initial evaluation is performed. Behavioral treatments should be the principal therapeutic approach. Medications can be carefully considered as adjunctive treatment options in selected clinical situations.

References 1. Hiscock H, Bayer J, Gold L, Hampton A, Ukoumunne OC, Wake M. Improving infant sleep and maternal mental health: a cluster randomised trial. Arch Dis Child. 2007;92(11):952–8. 2. Quach J, Gold L, Hiscock H, Mensah FK, Lucas N, Nicholson JM, et al. Primary healthcare costs associated with sleep problems up to age 7 years: Australian population-based study. BMJ Open. 2013;3(5). 3. Quach J, Oberklaid F, Gold L, Lucas N, Mensah FK, Wake M. Primary health-care costs associated with special health care needs up to age 7 years: Australian population-based study. J Paediatr Child Health. 2014;50(10):768–74. 4. Meltzer LJ, Plaufcan MR, Thomas JH, Mindell JA.  Sleep problems and sleep disorders in pediatric primary care: treatment recommendations, persistence, and health care utilization. J Clin Sleep Med. 2014;10(4):421–6. 5. Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A. Behavioral treatment of bedtime problems and night wakings in infants and young children. Sleep. 2006;29(10):1263–76. 6. De Bruin EJ, van Steensel FJ, Meijer AM. Cost-effectiveness of group and internet cognitive behavioral therapy for insomnia in adolescents: results from a randomized controlled trial. Sleep. 2016;39(8):1571–81. 7. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD, Clinical Guidelines Committee of the American College of P.  Management of chronic insomnia disorder in adults: a

120

R. Pelayo

clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125–33. 8. Paruthi S, Brooks LJ, D’Ambrosio C, Hall WA, Kotagal S, Lloyd RM, et al. Pediatric sleep duration consensus statement: a step forward. J Clin Sleep Med. 2016;12(12):1705–6. 9. Paruthi S, Brooks LJ, D’Ambrosio C, Hall WA, Kotagal S, Lloyd RM, et al. Consensus statement of the American Academy of Sleep Medicine on the recommended amount of sleep for healthy children: methodology and discussion. J Clin Sleep Med. 2016;12(11):1549–61. 10. Paruthi S, Brooks LJ, D’Ambrosio C, Hall WA, Kotagal S, Lloyd RM, et al. Recommended amount of sleep for pediatric populations: a consensus statement of the American Academy of Sleep Medicine. J Clin Sleep Med. 2016;12(6):785–6. 11. Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, et al. National Sleep Foundation’s sleep time duration recommendations: methodology and results summary. Sleep Health. 2015;1(1):40–3. 12. Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from infancy to adolescence: reference values and generational trends. Pediatrics. 2003;111(2):302–7. 13. American Academy of Sleep Medicine. The international classification of sleep disorders Third Edition. 3nd ed. Westchester: American Academy of Sleep Medicine; 2014. xviii, 383 pp. 14. Ferber R. Solve your child’s sleep problems. New York: Simon and Schuster; 1985. 251 p. 15. Picchietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens JA, et al. Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14(12):1253–9. 16. Simakajornboon N, Dye TJ, Walters AS. Restless legs syndrome/Willis-Ekbom disease and growing pains in children and adolescents. Sleep Med Clin. 2015;10(3):311–22. xiv 17. Morgenthaler TI, Owens J, Alessi C, Boehlecke B, Brown TM, Coleman J Jr, et al. Practice parameters for behavioral treatment of bedtime problems and night wakings in infants and young children. Sleep. 2006;29(10):1277–81. 18. Etherton H, Blunden S, Hauck Y. Discussion of extinction-based behavioral sleep interventions for young children and reasons why parents may find them difficult. J Clin Sleep Med. 2016;12(11):1535–43. 19. Brasure M, Fuchs E, MacDonald R, Nelson VA, Koffel E, Olson CM, et al. Psychological and behavioral interventions for managing insomnia disorder: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2016;165(2):113–24. 20. Gradisar M, Jackson K, Spurrier NJ, Gibson J, Whitham J, Williams AS, et  al. Behavioral interventions for infant sleep problems: a randomized controlled trial. Pediatrics. 2016;137(6). 21. Crichton GE, Symon B. Behavioral management of sleep problems in infants under 6 months – what works? J Dev Behav Pediatr. 2016;37(2):164–71. 22. Owens J, Adolescent Sleep Working G, Committee on A. Insufficient sleep in adolescents and young adults: an update on causes and consequences. Pediatrics. 2014;134(3):e921–32. 23. Keyes KM, Maslowsky J, Hamilton A, Schulenberg J. The great sleep recession: changes in sleep duration among US adolescents, 1991–2012. Pediatrics. 2015;135(3):460–8. 24. Crowley SJ, Van Reen E, LeBourgeois MK, Acebo C, Tarokh L, Seifer R, et al. A longitudinal assessment of sleep timing, circadian phase, and phase angle of entrainment across human adolescence. PLoS One. 2014;9(11):e112199. 25. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP Jr, Vitiello MV, et al. Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1460–83. 26. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP Jr, Vitiello MV, et al. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1484–501. 27. Wahlstrom KL, Owens JA.  School start time effects on adolescent learning and academic performance, emotional health and behaviour. Curr Opin Psychiatry. 2017;30(6):485–90. 28. Minges KE, Redeker NS. Delayed school start times and adolescent sleep: a systematic review of the experimental evidence. Sleep Med Rev. 2016;28:86–95.

9  Evaluation and Management of the Sleepless Child

121

29. Barnes M, Davis K, Mancini M, Ruffin J, Simpson T, Casazza K. Setting adolescents up for success: promoting a policy to delay high school start times. J Sch Health. 2016;86(7):552–7. 30. Adolescent Sleep Working G, Committee on A, Council on School H. School start times for adolescents. Pediatrics. 2014;134(3):642–9. 31. Thorpy MJ, Korman E, Spielman AJ, Glovinsky PB. Delayed sleep phase syndrome in adolescents. J Adolesc Health Care. 1988;9(1):22–7. 32. Magee M, Marbas EM, Wright KP Jr, Rajaratnam SM, Broussard JL.  Diagnosis, cause, and treatment approaches for delayed sleep-wake phase disorder. Sleep Med Clin. 2016;11(3):389–401. 33. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM.  Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015;11(10):1199–236. 34. Figueiro MG. Delayed sleep phase disorder: clinical perspective with a focus on light therapy. Nat Sci Sleep. 2016;8:91–106. 35. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et  al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15(3):434–43. 36. Zee PC. Shedding light on the effectiveness of melatonin for circadian rhythm sleep disorders. Sleep. 2010;33(12):1581–2. 37. Bruni O, Alonso-Alconada D, Besag F, Biran V, Braam W, Cortese S, et  al. Current role of melatonin in pediatric neurology: clinical recommendations. Eur J Paediatr Neurol. 2015;19(2):122–33. 38. Owens JA, Rosen CL, Mindell JA, Kirchner HL.  Use of pharmacotherapy for insomnia in child psychiatry practice: a national survey. Sleep Med. 2010;11(7):692–700. 39. Pelayo R, Yuen K.  Pediatric sleep pharmacology. Child Adolesc Psychiatr Clin N Am. 2012;21(4):861–83. 40. Erland LA, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275–81. 41. Grigg-Damberger MM, Ianakieva D. Poor quality control of over-the-counter melatonin: what they say is often not what you get. J Clin Sleep Med. 2017;13(2):163–5. 42. van Maanen A, Meijer AM, Smits MG, van der Heijden KB, Oort FJ. Effects of melatonin and bright light treatment in childhood chronic sleep onset insomnia with late melatonin onset: a randomized controlled study. Sleep. 2017;40(2). 43. Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Med. 2014;15(4):385–92. 44. Asano M, Ishitobi M, Kosaka H, Hiratani M, Wada Y.  Ramelteon monotherapy for insomnia and impulsive behavior in high-functioning autistic disorder. J Clin Psychopharmacol. 2014;34(3):402–3. 45. Richardson GS, Zee PC, Wang-Weigand S, Rodriguez L, Peng X.  Circadian phase-­ shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med. 2008;4(5):456–61. 46. Kawabe K, Horiuchi F, Oka Y, Ueno S.  The melatonin receptor agonist ramelteon effectively treats insomnia and behavioral symptoms in autistic disorder. Case Rep Psychiatry. 2014;2014:561071. 47. Sasayama D, Washizuka S, Honda H. Effective treatment of night terrors and sleepwalking with ramelteon. J Child Adolesc Psychopharmacol. 2016;26(10):948. 48. Keating GM. Tasimelteon: a review in non-24-hour sleep-wake disorder in totally blind individuals. CNS Drugs. 2016;30(5):461–8. 49. Johnsa JD, Neville MW.  Tasimelteon: a melatonin receptor agonist for non-24-hour sleep-­ wake disorder. Ann Pharmacother. 2014;48(12):1636–41. 50. Troester MM, Pelayo R.  Pediatric sleep pharmacology: a primer. Semin Pediatr Neurol. 2015;22(2):135–47.

122

R. Pelayo

51. Kotagal S. Treatment of dyssomnias and parasomnias in childhood. Curr Treat Options Neurol. 2012;14(6):630–49. 52. Schepis TS. Age cohort differences in the nonmedical use of prescription zolpidem: findings from a nationally representative sample. Addict Behav. 2014;39(9):1311–7. 53. Ford JA, McCutcheon J. The misuse of Ambien among adolescents: prevalence and correlates in a national sample. Addict Behav. 2012;37(12):1389–94. 54. Shusterman D, Baroody FM, Craig T, Friedlander S, Nsouli T, Silverman B, et al. Role of the allergist-immunologist and upper airway allergy in sleep-disordered breathing. J Allergy Clin Immunol Pract. 2017;5(3):628–39. 55. Fishbein AB, Vitaterna O, Haugh IM, Bavishi AA, Zee PC, Turek FW, et al. Nocturnal eczema: review of sleep and circadian rhythms in children with atopic dermatitis and future research directions. J Allergy Clin Immunol. 2015;136(5):1170–7. 56. Leger D, Bonnefoy B, Pigearias B, de La Giclais B, Chartier A. Poor sleep is highly associated with house dust mite allergic rhinitis in adults and children. Allergy Asthma Clin Immunol. 2017;13:36. 57. Seidman MD, Gurgel RK, Lin SY, Schwartz SR, Baroody FM, Bonner JR, et al. Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(1 Suppl):S1–43. 58. Ginis T, Akcan FA, Capanoglu M, Toyran M, Ersu R, Kocabas CN, et al. The frequency of sleep-disordered breathing in children with asthma and its effects on asthma control. J Asthma. 2017;54(4):403–10. 59. Sanchez T, Castro-Rodriguez JA, Brockmann PE. Sleep-disordered breathing in children with asthma: a systematic review on the impact of treatment. J Asthma Allergy. 2016;9:83–91. 60. Zandieh SO, Cespedes A, Ciarleglio A, Bourgeois W, Rapoport DM, Bruzzese JM. Asthma and subjective sleep disordered breathing in a large cohort of urban adolescents. J Asthma. 2017;54(1):62–8. 61. Mukhatiyar P, Nandalike K, Cohen HW, Sin S, Gangar M, Bent JP, et al. Intracapsular and extracapsular tonsillectomy and adenoidectomy in pediatric obstructive sleep apnea. JAMA Otolaryngol Head Neck Surg. 2016;142(1):25–31.

Evaluation and Management of Movement Disorders in Children

10

Luis E. Ortiz and Christopher Cielo

Sleep-related movement disorders are a highly variable group of conditions that are generally benign but need to be able to be distinguished from more serious conditions.

 eneral Assessment of Sleep-Related Movement G Disorders in Children Sleep-related movement disorders (SRMD) that can be found in children are reviewed here (Table 10.1). In general, the history obtained from the parents, and sometimes the patient, is diagnostic for SRMD. In addition to a thorough description, a video of the movements can also be very helpful. It is important to determine if these movements occur outside of sleep or the period of sleep onset as SRMD are typically restricted to this time. Complex movements or goal-directed actions that may present during sleep but can also present during wake include Tourette syndrome, dystonia, epilepsy, habitual self-soothing movements, or other mimickers of SRMD (Table 10.2). In cases where the diagnosis is not clear from history, the evaluation may benefit from polysomnography. Polysomnography is a standardized continuous video and multichannel recording of physiological parameters during sleep. These recordings usually occur overnight and in children are typically performed in an attended

L. E. Ortiz Sleep Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA C. Cielo (*) Sleep Center, Department of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Fishbein, S. H. Sheldon (eds.), Allergy and Sleep, https://doi.org/10.1007/978-3-030-14738-9_10

123

124

L. E. Ortiz and C. Cielo

Table 10.1  Features of sleep-related movement disorders Restless legs syndrome

Brief description Leg discomfort at night and rest, causing irresistible urge to move legs. Results in disrupted sleep or difficulty initiating sleep. Correlation with ADHD Repetitive, highly stereotyped limb movements. Results in frequent arousals leading to daytime symptoms. May precede RLS in children

Periodic limb movement disorder Sleep-related leg Leg cramping at night that can occur prior to or after sleep onset. Not cramps thought to be physiologically different from leg cramps in other situations but can be associated with medical conditions such as diabetes mellitus, dystonias, and metabolic derangements (hypokalemia, hypomagnesemia) Sleep-related Repetitive jaw clenching or grinding of teeth resulting in tooth wear or jaw bruxism pain/discomfort. Primary bruxism can be seen in normal, healthy children but can be associated with stress or anxiety. Secondary bruxism is often observed in children with cerebral palsy or mental retardation. High rate of OSA comorbidity Repetitive, stereotyped, and rhythmic (~2 movements/sec) motor behaviors Sleep-related such as body rocking and headbanging. Typically occurs at sleep onset but rhythmic can occur during quiet activities. Common in infants and tapers off in early movement childhood. Can persist through adulthood in developmentally normal disorder individuals Repetitive myoclonic jerks only during sleep in neurologically normal Benign sleep neonates and infants. Typically presents at age 1 month. Can occur with the myoclonus of whole body or isolated to the limbs, trunk, or face. Resolves between ages 3 infancy and 6 months

Table 10.2  Imitators of sleep-related movement disorders Autoerotic behaviors Tourette’s disorder Seizure Self-soothing repetitive motion REM behavior disorder, sleep walking, confusional/partial arousals, and other parasomnias

Brief description May involve body rocking or rhythmic movements but primary focus is genital stimulation Tics that occur during wake, may be present prior to sleep onset Stereotyped movements that may occur during wake and sleep May include thumb sucking Occur during sleep. Complex goal-oriented actions. Secondary to incomplete transition to sleep states or slow transition to wake

sleep laboratory. Polysomnography includes a video recording of the patient, a limited electroencephalogram used to stage sleep and score arousals, measures of airflow and respiratory effort, pulse oximetry to determine hypoxemia, and electromyography to detect leg and chin movements. Polysomnography is necessary to make the diagnosis of some conditions, such as periodic limb movement disorder. The limited electroencephalogram can be used to screen for seizure activity as well. In these cases, the video recording can be helpful in visualizing the

10  Evaluation and Management of Movement Disorders in Children

125

movements and correlating them with physiologic measures recorded during polysomnography and technician notes during the study.

Specific Sleep-Related Movement Disorders Restless Leg Syndrome Restless legs syndrome (RLS) is an almost irresistible urge to move the limbs, typically due to uncomfortable sensations deep in the limbs at night prior to sleep onset. This leads to delayed sleep onset and difficulty resuming sleep following arousals [1]. Per the ICSD, (1) symptoms must begin or worsen with rest or inactivity; (2) the uncomfortable sensations must be partially or completely relieved with movement; and (3) symptoms must have a circadian timing, with worsening symptoms at night. These symptoms cannot be explainable by other medical or behavioral issues (cramps, positional discomfort, habitual foot tapping). Finally, these symptoms must cause disruption of the health or daily functioning of the patient [1]. In children, the description of the symptoms should be in their own words. RLS is not as rare as previously thought, with 5–10% of European and North American adults expressing RLS symptoms. There is a higher prevalence in women and populations of European descendent. The mean age onset is during the third or fourth decade of life, with incidence increasing with age [2–6]. However, one-third of adult patients in two survey studies report symptom onset during childhood [5, 7, 8]. The pediatric prevalence is estimated to be 2–4% in the US and UK.  Unlike adults, there does not appear to be a gender difference in the prevalence of symptoms in children. In children, RLS is often comorbid with ADHD and “growing pains” [5, 9]. The pathophysiology of RLS is not fully understood. However, it is felt that under normal sleep conditions, spinal flexor reflexes and sensory activity of the limbs are suppressed through dopamine signaling [10–12]. This is demonstrated by improvement of symptoms with dopamine agonists, worsening of symptoms with dopamine antagonists, and dopamine receptor knockout animal models showing symptoms similar to RLS [12]. Iron metabolism has also been identified as a key factor in RLS pathology; patients with relative iron deficiency (ferritin 75 μg/L. A gradual taper of iron may begin once target levels have been reached with interval measurements of ferritin to screen for iron overload or return to an iron-deficient state. Constipation and abdominal pain are the most common side effects of iron therapy and can be treated with stool softeners. Other less common but worrisome side effects include dark stool and teeth staining. Iron repletion is contraindicated in children with disorders prone to iron overload such as hemolytic anemia, hemochromatosis, or the need for recurrent transfusion. Dopaminergic medications such as ropinirole or carbidopa/levodopa have a long history showing efficacy in treating RLS symptoms. Dopaminergic medications have not been well-studied for RLS in children, but side effects in adult patients include nausea, vomiting, hallucinations, and rarely development of obsessive-­ compulsive behaviors [22]. Most adults treated long term will eventually develop augmentation, which is escalating severity of symptoms due to dopamine receptor downregulation. Patients may also develop rebound symptoms with onset or worsening of symptoms once the medication is cleared of the body.

128

L. E. Ortiz and C. Cielo

Calcium channel α2δ-1 subunit ligands such as gabapentin or pregabalin are also approved for RLS in adults [15]. Developed for the treatment of epilepsy, these medications bind to voltage-gated ion channels to decrease presynaptic calcium currents and are also used in treatment of neuropathic pain in adults. While there are no prospective data in children, these ligands have a broad therapeutic profile and are used in the treatment of children with epilepsy. Side effects include sedation and dizziness. Pediatric dosing for gabapentin starts at 5 mg/kg/dose with titration of dose for effect. Benzodiazepines are often used to treat insomnia and have been used to treat RLS. Rather than decreasing the frequency of sensation/urge to move, it is thought that benzodiazepines result in increased sedation to improve sleep efficiency [23]. These medications can put children at risk for daytime sleepiness, behavior changes, and disruption of nocturnal breathing patterns. There is also the risk of developing dependence or drug subversion that makes benzodiazepine a less attractive option for the treatment of RLS, especially in children. Opioids have been shown to be effective in the management of severe, refractory RLS in adults. Like in benzodiazepines, its use is limited by side effects (respiratory suppression, sedation, behavior changes) as well as dependence risk.

Periodic Limb Movement Disorder Periodic limb movement disorder (PLMD) is a pattern of periodic episodes of limb movements that occur during and are disruptive to sleep. Periodic limb movements during sleep (PLMS) typically involve extension of the first digit of the foot with flexion of the ankle and knee. The hip may also be involved. These movements may be involved with cortical arousal. PLMS must occur at an increased frequency (more than 5/hour for children and 15/hour for adults), and these leg movements must cause clinically significant sleep disturbance or impaired daytime functioning for a diagnosis of PLMD [1]. Unlike RLS, where there is a conscious effort to move due to an uncomfortable sensation, patients with PLMD are typically unaware of the limb movements or sleep disruption. Despite being a separate disorder, it is thought that both disorders share a common pathophysiology. Both are associated with iron deficiency, respond to dopaminergic medications, and share many comorbidities (ADHD, mood disorder). Having a first-degree relative with RLS increases the risk for development of PLMD [1]. Many children with RLS develop PLMD or noticeable PLMS years before the symptoms of RLS are present [24]. PLMS can represent a normal part of aging as they are uncommon in youth ( Pds> Pcrit Normal unobstructed breathing Open upper airways

Pus

Pds

Upper (upstream) segment (US)

Lower (downstream) segment (LS) Collapsible segment

Pus> Pcrit> Pds Snoring, UARS, hypopnea Upper airway collapse with reduced airflow

Pus

Pds

Upper (upstream) segment (US)

Lower (downstream) segment (LS) Collapsible segment

Pcrit> Pus> Pds Obstructive apnea Complete occlusion of the upper airway, no airflow

Pus

Pds

Upper (upstream) segment (US)

Lower (downstream) segment (LS) Collapsible segment

Fig. 11.1  The upper airway can be represented as a mechanical analogue of the Starling resistor model, consisting of a rigid tube with a collapsible segment. The collapsible segment has no resistance but is subject to the surrounding pressure, Pcrit. Collapse occurs only when the surrounding pressure exceeds the downstream pressure and inspiratory airflow decreases compared to normal unobstructed breathing. Complete occlusion occurs when Pcrit exceeds both the upstream and downstream pressure. (From Kirkness et  al. [14]. Copyright © 2006. Karger Publishers, Basel, Switzerland, with permission.)

140

I. Donskoy and S. H. Sheldon

from congestion and inflammation results in negative intraluminal pressure that can surpass the critical closing pressure of the airway and lead to upper airway collapse. An older study was able to show that nasal resistance in patients with OSA is higher than in control subjects [15]. While there have been studies which suggest this mechanism, the data are somewhat controversial [16, 17]. Disparities may be explained by the heterogeneity of OSA: at times due to anatomy, muscle function, a low arousal threshold, or unstable control of ventilation [18]. While humans have one lower airway, there are two entry points: nose and mouth. Theoretically, inflammation or obstruction in one area may have impacts on the other. While allergic rhinitis resides in the nasal passage ways, tonsillar hypertrophy affects the oropharynx. With nasal obstruction, air is unable to enter and flow through this ideal laminar path, so the mouth is chosen instead. This is a physiologic reaction, but not an ideal substitute. Mouth breathing may be the first reported symptom in disordered breathing of sleep, noted even incidentally. However, mouth breathing alone has also been shown to have a negative impact on pulmonary function testing [19], irritate the airway due to cold dry air [20], and increase the inhalation of small particles including indoor aeroallergens [21]. Allergic rhinitis can be an easily identified culprit for mouth breathing. However, in a questionnaire-based study of adult subjects in Japan, mouth breathing was determined to be a risk factor for asthma independent of allergic rhinitis, pediatric asthma, or eosinophilia. When mouth breathing and allergic rhinitis were both reported, the odds ratio of a subject having asthma increased twofold [22]. Obstructive sleep apnea is a known correlate of poor control of asthma [23]. The presence of nocturnal asthma symptoms can lead to numerous awakenings at night [24]. In children, associations have been demonstrated between the number of nightly awakenings and poor school performance, school absences, and behavioral problems [25–27]. Napping is more common in children with asthma versus healthy controls [28] which is reflective of excessive daytime sleepiness. While there is a predisposition of patients with asthma to develop sleep disordered breathing (SDB), in children who were already diagnosed with SDB, the odds ratio of having severe asthma was increased by 3.62 [29], suggesting bidirectionality. Disrupted sleep can cause asthma symptom exacerbation, while improved sleep may mediate symptoms. A self-reported increased quantity of sleep demonstrated an improvement in peak expiratory flow in children with asthma [30]. However, timing and causation is challenging to tease out. It was previously shown that obstructive sleep apnea prevalence is increased in asthmatics and that control of the OSA allows for improved control of asthma symptoms in children [12, 13, 18, 25, 26]. In a recent study, the presence of asthma history was associated with significantly more adenotonsillar regrowth [31], leading to increased airway obstruction and the potential for respiratory-driven sleep disruption, suggesting a two-way interaction. In a longitudinal twin study [32] where children were questioned at two points (around 8 and then 13 years of age), some insight into this relationship was revealed. Being overtired, regardless of the reason, at younger ages was associated with asthma and rhinitis at older ages. If asthma symptoms were controlled, the correlation disappeared (although having symptoms of asthma at a younger age was associated with being overtired, having a short sleep time, and trouble sleeping later

11  Evaluation and Management of Allergic Disorders Related to Sleep Pathology

141

on in life). However, control of rhinitis symptoms was irrelevant, and disrupted sleep was an independent predictor of developing or continuing to endorse rhinitis symptoms. Fortunately, the treatment of sleep disordered breathing, as well as that of allergic disorders, is well studied and regimented. A stepwise approach to investigating sleep disordered breathing [33, 34], includes polysomnography to determine the severity. If obstructive sleep apnea is diagnosed, it can be further classified into mild, moderate, or severe. Depending on severity and comorbidities, at least in pediatrics, often removal of the tonsils and adenoids (adenotonsillectomy, T&A) is pursued, with the assumption that airway obstruction is a prominent mechanism for SDB. Uncontrolled allergy symptoms can lead to congestion and inflammation that will further impair nocturnal airflow, and OSA alone can feed back causing sleep disruption worsening allergic disease burden. It is to be concluded that optimizing the treatment of allergic and sleep disorders is imperative to have the best overall results for both disease processes. Studies have looked at the use of montelukast and intranasal steroids in the postoperative period for treating residual OSA after adenotonsillectomy. In theory, these anti-inflammatory medications systemically or locally (respectively) serve to decrease the size of glandular tissue which may obstruct normal breathing [35]. There have been demonstrated improvements in overall outcome after T&A with this adjunctive treatment of OSA, but this may have been treating an underlying allergic rhinitis which would otherwise have predisposed the patient to adenotonsillar regrowth [36]. Regardless, the importance of controlling allergic rhinitis is paramount for the short- and long-­term efficacy of the surgical treatment of pediatric OSA. Intranasal corticosteroids can improve the quality of sleep and reduction in symptoms in patients with OSA [37, 38]. While corticosteroids have been shown to improve symptoms, sleep, and daytime energy in patients with AR [38, 39–41], sedating medications such as antihistamines in the daytime may actually worsen already poor performance in school due to their sedating side effects. Caution should be taken when trying to improve allergic symptoms, not to compound further daytime sleepiness in a child who may likely also have a sleep pathology.

Dermatologic Perspective An increase in respiratory events from nasal or oropharyngeal obstruction is not the only way in which allergic disease can disrupt sleep. Eczema (atopic dermatitis) is an inflammatory skin disorder that manifests as pruritus which can lead to distress during the day and nighttime [42]. In the past, actigraphy has shown that patients with eczema move more at night, suggesting less time in sleep and more in wake, leading to decreased sleep efficiency [43, 44]. While it may be tempting to attribute this to arousals related to itching due to pruritus, subjects with eczema still show decreased sleep quality even with well controlled symptoms [45]. Concurrently having a diagnosis of eczema and a sleep disorder increases the risk of psychological comorbidities as well as outcomes of excessive daytime

142

I. Donskoy and S. H. Sheldon

sleepiness such as motor vehicle accidents and injury [8, 16]. A large study in adults in 2015 found that a reported eczema diagnosis in the last year was associated with a higher odds ratio of a shorter or longer than average sleep duration, even when controlling for other allergic disease [5]. While a short sleep duration suggests fragmented/disrupted sleep, a long sleep duration may be a downstream manifestation of disrupted sleep (excessive sleepiness) as well as potentially being due to the use of sedating antihistamines for symptom control. Upon sub-analysis, there were two groups of patients with eczema: ones with other sleep comorbidities including insomnia, fatigue, and daytime sleepiness and another with only a higher probability of insomnia [5]. The question of why some sufferers of eczema have a more drastic impact on their sleep and energy is an intriguing one, suggesting that there may be a way to individualize therapy. Similar to varying OSA phenotypes [46], there may be differences among the different types of eczema [47] that have a range of effects on sleep and, in turn, daytime functioning. There is a significant two-way interaction noted between sleep and atopic dermatitis. While the symptoms of eczema can disrupt sleep, complaints of daytime sleepiness, insomnia, but more notably the combination of the two, increase the odds ratio of having eczema by a factor of three [5]. Perhaps there is a downstream effect from poor-quality sleep which can precipitate eczema in susceptible individuals.

Immunologic Perspective It becomes clear from looking at mechanical disruptors of sleep and physiologic triggers for asthma, allergic rhinitis, and atopic dermatitis that there are other, more subtle, forces at play in how the pathologies of sleep and allergic disease correlate. Fatigue, even in the absence of disordered sleep, has been reported in association with allergic disease [48, 49], and teasing apart fatigue from the lack of quality sleep is challenging. Determining the chronologic relationship between allergic disease and sleep disruption leading to daytime sleepiness is also not simple. Children with positive allergy tests are more likely to have obstructive sleep apnea [50]. It is theorized that an allergic disease process leads to growth of lymphoid tissue (like tonsils and adenoids) increasing their size and risk of obstruction leading to respiratory symptoms. Recent analyses have added more evidence to this hypothesis, showing that the presence of reported history of allergic disease in young patients, and even more so in older children, is a risk factor for adenotonsillar regrowth after surgery [31]. This suggests that the development of allergic disease and exposure to specific triggers has long-term outcomes for the quality of sleep these patients will have. However, upon immunologic analysis of tissue from subjects who had adenotonsillar regrowth, there was no significant difference in the amount of total leukocytes and CD4+ T cells [31]. There was a significant increase in the serum IgE, suggesting that although the amount of leukocytes is not significantly different, their function and downstream production of inflammatory mediators certainly are. Interestingly, there was also a decrease in FoxP3 and an increase in GATA3+ in tissue from subjects with adenotonsillar regrowth. FoxP3 (forkhead box P3) is a transcription factor that

11  Evaluation and Management of Allergic Disorders Related to Sleep Pathology

143

promotes the differentiation of Th0 cells into regulatory T cells (Tregs) which are integral to the suppression of immune reactions [51]. Interestingly, sleep deprivation alone can disrupt regulatory T cell function [52]. On the other hand, GATA3+ is a transcription factor expressed by a specific type of helper T cells (Th2) which feeds back to help more Th0 cells differentiate into the Th2 subtype [53]. This shift to more Th2 CD4+ cells is thought to be the driving factor behind allergic disease (Fig. 11.2) [54, 55]. It is this suppression of mediation from FoxP3 as well as a GATA3+-driven increase in the Th2 cell type which promotes allergic reactivity, inflammation, and possibly adenotonsillar regrowth. This may lead to overall airway inflammation and respiratory disruption [56]. It may also promote the release of downstream cytokines, which have been correlated with decreased sleep latency (a sign of increased sleepiness) as well as increased REM latency and less time in REM sleep (a sign of poorquality sleep) [57]. This fits with previously self-reported difficulties with sleep onset, maintenance, and sleep disruption in patients with allergic rhinitis [58]. It suggests that something inherent in the allergic process can decrease sleep quality and impact daytime functioning. An exciting new research avenue being explored is the role of yet another CD4+ cell type, the Th17 subset. These cell types play an important role in promoting allergic and autoimmune disease and have been shown to be correlated with subjects who have sleep disordered breathing from OSA [59]. It is theorized that repeat infections or exposures to infectious triggers promotes Th17 recruitment and that, over time, reactive tissue increases in size, causing sleep disordered breathing [59]. However, the downregulation of Tregs from sleep deprivation further skews the Th17/Treg ratio and leads to an even further unchecked inflammatory cascade, which impairs control of systemic allergic symptoms, leading back to increased physical impedance of nocturnal breathing needed for quality sleep. Effector T cells Th1

Regulatory T cells (tregs)

INF-g Cellular immunity Autoimmunity

IL-12, INF-g Th2 Naturally occuring tregs (CD4+CD25+ FOXP3,CD8+CD122+)

IL-4

IL-4 & IL-10 Humoral immunity allergy

naive CD4+ T cell Th17

TGF-b, IL-10? Inducible tregs Tr1, Th3

IL-6, TGF-b

IL-17 Inflammation Autoimmunity

Fig. 11.2  The differentiation of CD4+ cells into specific T cell subsets. (From Rydzewska et al. [70], with permission.)

144

I. Donskoy and S. H. Sheldon

Circadian Perspective The circadian rhythms that regulate sleep also regulate many other bodily processes including hormone synthesis [1]. The nadir of cortisol secretion is in the night and this dip alters the inflammatory pathway (Fig. 11.3) [60]. Many allergic processes are prevented and treated with exogenous steroid to modulate the immune reaction, and the absence of endogenous cortisol in the night often leads to peaks of symptoms of asthma exacerbations and allergic rhinitis [61, 62]. In subjects with atopic dermatitis, there is also a rhythm to transepidermal water loss which has a peak in the evening, and this topical dehydration may lead to increased pruritus, causing sleep onset issues and sleep maintenance insomnia [63]. Histamine, a mediator of allergic reactions, is present in the wake state, and targeted therapies may promote drowsiness and actually treat insomnia. As allergic symptoms flare in the night, with more histamine release from mast cells, this disrupts sleep at the central nervous system level [64] and causes a waking state (Fig. 11.4). Some early pharmacologic studies have begun to utilize circadian rhythms in the optimal dose timing for medication [65], and this may be a future avenue to explore in the treatment of allergic disease. Interestingly, while there is a circadian rhythm to certain cytokines such as IL-2, there is more of a sleep-­dependent rhythm to the expression of regulatory T cells that

Plasma cortisol 350

Amount (nmol/L)

300 250 200 150 100 50 0

11 pm 12 am 1 am 2 am 3 am 4 am 5 am 6 am 7 am 11 am 3 pm 6 pm 7 pm

Time of day

Fig. 11.3  The mean changes in human plasma cortisol over a 24-hour period, with a nadir in the night. (Adapted from Axelsson et al. [71].)

11  Evaluation and Management of Allergic Disorders Related to Sleep Pathology

145

CSF histamine

Amount (pg/mL)

50 45 40 35 30 25 20 15 10 5 0

10 am

1 pm

4 pm

7 pm

11 pm

1 am

4 am

Time of day

Fig. 11.4  The mean changes in CSF histamine over a 24-hour period in squirrel monkeys, who have a similar consolidated active/wake state in the daytime. A nadir in histamine can be seen during sleep. (Adapted from Zeitzer et al. [72]. Reprinted by Permission of SAGE Publications, Ltd., with permission.)

may mitigate the inflammatory cascade [52]. This suggests that although some of the fluctuations of inflammation are circadian and beyond an individual’s control, ensuring quality and quantity of nocturnal sleep could be a big factor in easing symptom burden.

Positive Perspective There has been a largely negative focus on the relationship between the presence of disordered sleep and allergic disease. However, some recent literature has shed light on another perspective. Narcolepsy is a disorder of sleep dysregulation in both sleep and wake which manifests as excess daytime sleepiness, hypnagogic and hypnopompic hallucinations, sleep paralysis, and in certain types, cataplexy [66]. On an MSLT (multiple sleep latency test), patients will characteristically have a short mean sleep latency over a series of daytime naps, even after a full night of sleep, and at least two sleep onset REM periods (SOREMPs) during those naps. Type 1 narcolepsy (with cataplexy) pathophysiology which involves loss of orexin (also known as hypocretin)-producing neurons in the lateral hypothalamus, at times without a clear cause. Type 2 narcolepsy has an even more elusive

146

I. Donskoy and S. H. Sheldon

pathophysiology, with no objective decrease in orexin nor any presence of cataplexy symptoms. There is a strong argument made for an underlying immunologic cause of narcolepsy, especially given its seasonal variation, associations with ASO titers, and an impressive peak during the H1N1 influenza outbreak in 2009 [67]. Both types of narcolepsy have a strong association with the HLA-DQB1*0602 allele but also with a demonstrated presence of Th2 lymphocytes [68]. When activated, T cells have the ability to attack targets and damage cells such as in the lateral hypothalamus, a theorized immunologic mechanism behind narcolepsy type 1 [69]. However, in a large multicenter study looking at over 400 cases of pediatric narcolepsy, subjects with type 1 narcolepsy had a lower frequency of asthma and allergic rhinitis (although not atopic dermatitis), suggesting a shift away from a Th2 cell type balance. Those subjects with concurrent type 1 narcolepsy and a diagnosed allergic disorder had longer mean sleep latency on MSLT, and the number of SOREMs was decreased, suggesting a milder phenotype. In other words, the presence of allergies (the shift toward more Th2) was a mitigating factor in the severity of the narcolepsy with cataplexy. This adds to the complexity of the interplay between sleep and allergic disease, whereas they are thought to impede the other, this is an example of symptom reduction. This is important in that it may make symptoms more subtle in new-onset narcolepsy if there is an underlying allergic condition. One may need to have a higher index of suspicion regarding new symptoms of fatigue or sleepiness in a patient with known allergic disease. The interplay between allergic disease and sleep pathology is intricate and likely bidirectional. There is a great deal of data demonstrating the impact that respiratory and dermatologic symptoms of specific allergic diseases such as asthma, rhinitis, and dermatitis have on sleep efficiency. Disruption to sleep, in turn, can cause a worsening of allergic symptoms. There is also a cascade of inflammatory players that comes along with allergic conditions (regardless of whether or not symptoms are controlled) which is disruptive to sleep and can feed back to exacerbate overall inflammation and allergic symptoms. Not to be excluded are the notable circadian and sleep/wake patterns of cortisol and histamine, respectively, which can provoke or protect against allergic flares. Some early pharmacologic studies have begun to utilize circadian timing in optimal dose administration [1], and this may be a future avenue to exploration of the treatment of allergic disease. While worsening of allergic or sleep pathology will usually lead to a negative shift in the other, there is also an unexpected attenuation of symptoms of a certain type of narcolepsy in the presence of allergic disease. Finally, adding to this complexity is the fact that, as with any physiologic balance, there is a great deal of individual variation. Some patients with atopic dermatitis seem particularly sensitive to sleep disruption, and others are more resilient to the impact their disorder has on sleep. Some patients with sleep disordered breathing, even after surgical intervention, may or may not have glandular regrowth due to persistent inflammatory markers, while others recover completely even with a personal reported history of atopy [66]. Individualization will be a key moving forward, in understanding the specific sleep and allergic

11  Evaluation and Management of Allergic Disorders Related to Sleep Pathology

147

issues that patients are suffering from, being conscientious in screening for one when the other is present, and tailoring management to ensure the optimization of both types of disorders.

References 1. Preußner M, Heyd F. Post-transcriptional control of the mammalian circadian clock: implications for health and disease. Pflugers Arch. 2016;468(6):983–91. 2. 2015 National Health Interview Survey (NHIS) data, Table 3-1 and Table 4-1. 3. Mastronarde JG, Wise RA, Shade DM, et al. Sleep quality in asthma: results of a large prospective clinical trial. J Asthma. 2008;45:183–9. 4. Summary health statistics tables for U.S. adults: National Health Interview Survey, 2015, Table A-2 5. Silverberg JI, et  al. Sleep disturbances in adults with eczema are associated with impaired overall health: a US population-based study. J Invest Dermatol. 2015;135(1):56–66. 6. Matricciani L, et al. Children's sleep needs: is there sufficient evidence to recommend optimal sleep for children? Sleep. 2013;36(4):527–34. 7. Gander PH, Marshall NS, Harris RB, et al. Sleep, sleepiness and motor vehicle accidents: a national survey. Aust NZ J Public Health. 2005;29:16–21. 8. Akerstedt T, Fredlund P, Gillberg M, et al. A prospective study of fatal occupational accidents— relationship to sleeping difficulties and occupational factors. J Sleep Res. 2002;11:69–71. 9. Wright RJ, Cohen RT, Cohen S. The impact of stress on the development and expression of atopy. Curr Opin Allergy Clin Immunol. 2005;5:23–9. 10. Chida Y, Hamer M, Steptoe A. A bidirectional relationship between psychosocial factors and atopic disorders: a systematic review and meta-analysis. Psychosom Med. 2008;70:102–16. 11. Berry RB, Brooks R, Gamaldo CE, Hardling S, Marcus C, Vaughn B. The AASM manual for the scoring of sleep and associated events. Rules, terminology and technical specifications. Darien: American Academy of Sleep Medicine; 2012. 12. Kannan JA, et  al. Parental snoring and environmental pollutants, but not aeroallergen sensitization, are associated with childhood snoring in a birth cohort. Pediatr Allergy Immunol Pulmonol. 2017;30(1):31–8. 13. Loekmanwidjaja J, et al. Sleep disorders in children with moderate to severe persistent allergic rhinitis. Braz J Otorhinolaryngol. 2018;84:178–84; J Sleep Res. 2002;11: 69–71. 14. Kirkness JP, Krishnan V, Patil SP, Schneider H. Upper airway obstruction in snoring and upper airway resistance syndrome. In: Randerath WJ, Sanner BM, Somers VK, editors. Sleep apnea. Basel: Karger; 2006. p. 79–89. 15. Blakley B, Mahowald M. Nasal resistance and sleep apnea. Laryngoscope. 1987;97(6):752–4. 16. Young T, Finn L, Kim H. Nasal obstruction as a risk factor for sleep disordered breathing. J Allergy Clin Immunol. 1997;99(2):S757–62. 17. Koutsourelakis I, Georgoulopoulos G, Perraki E, Vagiakis E, Roussos C, Zakynthinos SG. Randomised trial of nasal surgery for fixed nasal obstruction in obstructive sleep apnoea. Eur Respir J. 2008;31(1):110–7. 18. Eckert DJ.  Phenotypic approaches to obstructive sleep apnoea: new pathways for targeted therapy. Sleep Med Rev. 2016;37:45–59. 19. Hallani M, Wheatley JR, Amis TC. Enforced mouth breathing decreases lung function in mild asthmatics. Respirology. 2008;13:553–8. 20. Paul DW, Bogaard JM, Hop WC. The bronchoconstrictor effect of strenuous exercise at low temperatures in normal athletes. Int J Sports Med. 1993;14:433–6. 21. Environmental Protection Agency. Integrated science assessment for particulate matter: 2009 final report. Available from: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=216546.

148

I. Donskoy and S. H. Sheldon

22. Izuhara Y, et al. Mouth breathing, another risk factor for asthma: the Nagahama study. Allergy. 2016;71(7):1031–6; Eur Respir J. 1995;8:2076–80. 23. Qiao YX, Xiao Y. Asthma and obstructive sleep apnea. Chin Med J. 2015;128(20):2798–804. 24. Koinis-Mitchell D, Craig T, Esteban CA, Klein RB. Sleep and allergic disease: a summary of the literature and future directions for research. J Allergy Clin Immunol. 2012;130(6):1275– 81. https://doi.org/10.1016/j.jaci.2012.06.026. 25. Young T, Finn L, Kim H, The University of Wisconsin Sleep and Respiratory Research Group. Nasal obstruction as a risk factor for sleep-disordered breathing. J Allergy Clin Immunol. 1997;99:S757–62. 26. Horner CC, Mauger D, Strunk RC, Graber NJ, Lemanske RF Jr, Sorkness CA, et  al. Most nocturnal asthma symptoms occur outside of exacerbations and associate with morbidity. J Allergy Clin Immunol. 2011;128:977–82.e1-2. 27. Fagnano M, van Wijngaarden E, Connolly HV, Carno MA, Forbes-Jones E, Halterman JS, et al. Sleep-disordered breathing and behaviors of inner-city children with asthma. Pediatrics. 2009;124:218–25. 28. Kieckhefer GM, Ward TM, Tsai SY, Lentz MJ. Nighttime sleep and daytime nap patterns in school age children with and without asthma. J Dev Behav Pediatr. 2008;29:338–44. 29. Ross KR, Storfer-Isser A, Hart MA, Kibler AM, Rueschman M, Rosen CL, et  al. Sleep-­ disordered breathing is associated with asthma severity in children. J Pediatr. 2012;160:736–42. 30. Hanson MD, Chen E. The temporal relationships between sleep, cortisol, and lung functioning in youth with asthma. J Pediatr Psychol. 2008;33:312–6. 31. Huo Z, et al. The relationship between allergic status and adenotonsillar regrowth: a retrospective research on children after adenotonsillectomy. Sci Rep. 2017;7:46615. 32. Jernelov S, et al. Development of atopic disease and disturbed sleep in childhood and adolescence--a longitudinal population-based study. Clin Exp Allergy. 2013;43(5):552–9. 33. Sheldon K. Ferber, and Gozal. Principles and practice of pediatric sleep medicine. London: Saunders; 2014. 34. Farber JM. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2002;110(6):1255–7; author reply 1255–57. 35. Kuhle S, Urschitz MS.  Anti-inflammatory medications for obstructive sleep apnea in children. Cochrane Database Syst Rev. 2011;(1):CD007074. https://doi.org/10.1002/14651858. CD007074.pub2. 36. Kheirandish L, Goldbart AD, Gozal D. Intranasal steroids and oral leukotriene modifier therapy in residual sleep-disordered breathing after tonsillectomy and adenoidectomy in children. Pediatrics. 2006;117:e61–6. https://doi.org/10.1542/peds.2005-0795. 37. Gurevich F, Glass C, Davies M, Wei W, McCann J, Fisher L, et al. The effect of intranasal steroid budesonide on the congestion-related sleep disturbance and daytime somnolence in patients with perennial allergic rhinitis. Allergy Asthma Proc. 2005;26:268–74. 38. Hughes K, Glass C, Ripchinski M, Gurevich F, Weaver TE, Lehman E, et al. Efficacy of the topical nasal steroid budesonide on improving sleep and daytime somnolence in patients with perennial allergic rhinitis. Allergy. 2003;58:380–5. 39. Kakumanu S, Glass C, Craig T. Poor sleep and daytime somnolence in allergic rhinitis: significance of nasal congestion. Am J Respir Med. 2002;1:195–200. 40. Craig TJ, Sherkat A, Safaee S.  Congestion and sleep impairment in allergic rhinitis. Curr Allergy Asthma Rep. 2010;10:113–21. 41. Lunn M, Craig T. Rhinitis and sleep. Sleep Med Rev. 2011;15:293–9. 42. Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol. 2005;22:192–9. 43. Bender BG, Leung SB, Leung DY. Actigraphy assessment of sleep disturbance in patients with atopic dermatitis: an objective life quality measure. J Allergy Clin Immunol. 2003;111:598–602. 44. Camfferman D, Kennedy JD, Gold M, et al. Eczema and sleep and its relationship to daytime functioning in children. Sleep Med Rev. 2010;14:359–69. 45. Reuveni H, Chapnick G, Tal A, et al. Sleep fragmentation in children with atopic dermatitis. Arch Pediatr Adolesc Med. 1999;153:249–53.

11  Evaluation and Management of Allergic Disorders Related to Sleep Pathology

149

46. Eckert DJ. Phenotypic approaches to obstructive sleep apnoea – new pathways for targeted therapy. Sleep Med Rev. 2018;37:45–59. 47. Abuabara K, Margolis DJ. Do children really outgrow their eczema, or is there more than one eczema? J Allergy Clin Immunol. 2013;132:1139–40. 48. Benninger MS, Benninger RM. The impact of allergic rhinitis on sexual activity, sleep, and fatigue. Allergy Asthma Proc. 2009;30:358–65. 49. Marshall PS, O’Hara C, Steinberg P. Effects of seasonal allergic rhinitis on fatigue levels and mood. Psychosom Med. 2002;64:684–91. 50. McColley SA, Carroll JL, Curtis S, Loughlin GM, Sampson HA. High prevalence of allergic sensitization in children with habitual snoring and obstructive sleep apnea. Chest. 1997;111:170–3. 51. Togashi Y, Nishikawa H. Regulatory T cells: molecular and cellular basis for immunoregulation. Curr Top Microbiol Immunol. 2017;410:3–27. 52. Bollinger T, Bollinger A, Skrum L, Dimitrov S, Lange T, Solbach W. Sleep-dependent activity of T cells and regulatory T cells. Clin Exp Immunol. 2009;155:231–8. 53. Barnes PJ. Role of GATA-3 in allergic diseases. Curr Mol Med. 2008;8(5):330–4; J Pediatr. 2012;160:736–742. 54. Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol. 1999;17:255–81. 55. Townley RG, Horiba M. Airway hyperresponsiveness: a story of mice and men and cytokines. Clin Rev Allergy Immunol. 2003;24:85–110. 56. Braunstahl GJ, Hellings PW. Nasobronchial interaction mechanisms in allergic airways disease. Curr Opin Otolaryngol Head Neck Surg. 2006;14:176–82. 57. Krouse HJ, Davis JE, Krouse JH.  Immune mediators in allergic rhinitis and sleep. Otolaryngol Head Neck Surg. 2002;126(6):607–13; J Allergy Clin Immunol. 1997;99(suppl): S757–S62. 58. Meltzer E, Gross GN, Katial R, Storms W. Allergic rhinitis substantially impacts patient quality of life: findings from the nasal allergy survey assessing limitations. J Fam Pract. 2012;61(2 Suppl):S5–10. 59. Ni K, et  al. Th17/Treg balance in children with obstructive sleep apnea syndrome and the relationship with allergic rhinitis. Int J Pediatr Otorhinolaryngol. 2015;79(9):1448–54. 60. Meijer G, Postma D, Wempe J, Gerristen J, Knol K, van Aadleren W.  Frequency of nocturnal symptoms in asthmatic children attending a hospital out-patient clinic. Eur Respir J. 1995;8:2076–80. 61. Martin R, Banks-Schlegel S.  Chronobiology of asthma. Am J Respir Crit Care Med. 1998;158:1002–7. 62. Kelsay K. Management of sleep disturbance associated with atopic dermatitis. J Allergy Clin Immunol. 2006;118:198–201. 63. Gupta MA, Gupta AK. Sleep-wake disorders and dermatology. Clin Dermatol. 2013;31:118–26. 64. Tashiro M, Mochizuki H, Iwabuchi K, Sakurada Y, Itoh M, Watanabe T, et al. Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain. Life Sci. 2002;72:409–14. 65. Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, Supronik J, Szombati I, Romer U, Witte S, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013;72:204–10. 66. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–62. 67. Barateau L, et al. Narcolepsy type 1 as an autoimmune disorder: evidence, and implications for pharmacological treatment. CNS Drugs. 2017;31(10):821–34. 68. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41:708–11. 69. Fontana A, Gast H, Reith W, Recher M, Birchler T, Bassetti CL. Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss? Brain. 2010;13:1300–11.

150

I. Donskoy and S. H. Sheldon

70. Rydzewska M, Jaromin M, Pasierowska IE, Stożek K, Bossowski A. Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases. Thyroid research. 2018;11:2. 71. Axelsson J, Rehman J, Akerstedt T, et al. Effects of sustained sleep restriction on mitogen-­ stimulated cytokines, chemokines and T helper 1/T helper 2 balance in humans. Mongrain V, ed. PLoS ONE. 2013;8(12):e82291. 72. Zeitzer JM, et al. Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey. J Sleep Res. 2012;21(2):189–94.

Part III Asthma

Sleep-Related Disturbances Commonly Associated with Asthma

12

Sofia Konstantinopoulou and Ignacio E. Tapia

Nocturnal Asthma: Definition and Pathophysiology Asthma is a chronic inflammatory disease of the lower respiratory tract characterized by bronchial hyperreactivity and episodic partially reversible lower airway obstruction. Asthma is one of the most common chronic respiratory diseases of childhood [1], affecting 9.3% of children 14 years of age and younger [2]. Despite evidence-based guidelines for the evaluation and treatment of asthma, the impact of asthma on quality of life and health cost of patients is very high [3–6]. Frequency of missed sleep due to asthma symptoms is commonly used as indicator of asthma morbidity [7]. Difficulty initiating or maintaining sleep, related to asthma symptoms, may in fact reflect poorly controlled asthma. For instance, a child with asthma may wake up often during sleep either because of persistence of symptoms [8], inappropriate medication control [9], lack of adherence to the medical regimen, or exposure to household environmental allergens [10]. Many asthmatics experience worsening of their symptoms at night, and up to 90% report wheezing or nocturnal cough [11]. These symptoms may be related to functional changes in ventilation during sleep as asthmatics have greater loss of functional residual capacity (FRC), peak expiratory flow rates (PEFR), and tidal volume during sleep than normal subjects [12]. The severity of the morning decline in PEFR is closely correlated with higher lower airway resistance and its duration during sleep. Other S. Konstantinopoulou Division of Pulmonary Medicine, Department of Pediatrics, Sheikh Khalyfa Medical City, Tibbiyya, Abu Dhabi, United Arab Emirates I. E. Tapia (*) Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Sleep Center, Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Fishbein, S. H. Sheldon (eds.), Allergy and Sleep, https://doi.org/10.1007/978-3-030-14738-9_12

153

154

S. Konstantinopoulou and I. E. Tapia

factors which contribute to the pathophysiology of nocturnal bronchoconstriction include decreased inspiratory muscle activity, direct effect of cold air on airway tone, decreased mucociliary clearance, enhanced bronchial hyper-responsiveness due to increased parasympathetic tone [13], and hormonal changes such as increased levels of histamine [14].

Nocturnal Asthma Related to Sleep Disturbances Patients with nocturnal asthma symptoms are likely to have frequent arousals during sleep and report worse sleep quality [15]. For example, asthmatic adults compared to controls have reported less sleep time and sleep efficiency and greater time awake after sleep onset (WASO) [16]. In another study performed in adults, 12 asthmatic volunteers with nocturnal symptoms were compared with 10 age-matched control subjects. Each subject spent two consecutive nights in the sleep lab; the first night was considered acclimatization to the laboratory environment. The data collected from the second night indicated increased wake time, decreased mean sleep time, and increased number of awakenings in asthmatic subjects compared to normal subjects. There was no significant difference in sleep latency and percentage of REM sleep. However, there was markedly decreased slow wave sleep, which was replaced by stage 2 and stage 1 sleep, in the asthmatic group [17]. Several studies have shown similar findings in children with asthma. For example, in a sample of urban children with asthma, night waking from asthma occurred in 40% of the sample during a 1-month period [18]. Moreover, the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study provided a better example of sleep disturbances related to asthma. Parents of 2529 children aged 11 years who participated in PIAMA reported asthma symptoms such as wheezing, dyspnea, prescription of inhaled corticosteroids, and asthma diagnosis; and children reported subjective and objective characteristics of their sleep such as bedtime, rise time, sleep quality, and daytime sleepiness [19]. Data were analyzed based on asthma symptoms. Children without asthma symptoms rarely reported daytime sleepiness in contrast to children with asthma symptoms (43% vs. 29.2%, p